Pharmaceutical solution of amlodipine

ABSTRACT

Disclosed herein is a liquid pharmaceutical formulation substantially free of water, comprising: (i) amlodipine or a pharmaceutically acceptable salt thereof, (ii) at least one pharmaceutically acceptable excipient, and (iii) a sufficient amount of a vehicle comprising glycerin. Also disclosed herein is a liquid pharmaceutical formulation substantially free of water and ethanol, comprising: (i) amlodipine or a pharmaceutically acceptable salt thereof, (ii) at least one pharmaceutically acceptable excipient, and (iii) a sufficient amount of a vehicle comprising glycerin.

RELATED APPLICATION

This application claims priority to U.S. Provisional Patent ApplicationNo. 63/144,021, filed on Feb. 1, 2021.

FIELD

The disclosure relates to an oral pharmaceutical solution comprisingamlodipine or a pharmaceutically acceptable salt thereof.

BACKGROUND

High blood pressure or hypertension is a common condition in which thelong-term force of the blood against artery walls is high enough that itmay eventually cause health problems, such as heart disease. Bloodpressure is determined both by the amount of blood pumped by the heartand the amount of resistance to blood flow in arteries. Pumping bloodthrough narrowed arteries may result in high blood pressure or evenhypertension. Although a hypertensive patient may be asymptomatic,long-lasting vascular and heart damage may occur. Uncontrolled highblood pressure increases the risk of serious health problems, includingheart attack and stroke. Hypertension generally develops over manyyears, and it affects nearly everyone eventually. Fortunately,hypertension may be detected easily, and once detected, one can workwith your doctor to control it.

Many blood pressure medications, known as antihypertensives, areavailable by prescription to lower high blood pressure or hypertension.There are a variety of classes of high blood pressure medications andthey include a number of different drugs and can be broadly classifiedby the following classes: Diuretics, Beta-blockers, ACE inhibitors,Angiotensin II receptor blockers, Calcium channel blockers, Alphablockers, Alpha-2 Receptor Agonists, Combined alpha and beta-blockers,Central agonists, Peripheral adrenergic inhibitors, and Vasodilators.

Amlodipine is an angioselective calcium channel blocker and inhibits themovement of calcium ions into vascular smooth muscle cells and cardiacmuscle cells which inhibits the contraction of cardiac muscle andvascular smooth muscle cells. Amlodipine is available in different saltslike amlodipine besylate, amlodipine maleate, amlodipine orotate,amlodipine adipate, amlodipine camsylate, amlodipine nicotinate, andmany more. Amlodipine is referred to by the chemical name3-ethyl-5-methyl(±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylatewith a CAS No. of 88150-42-9, and with the following chemical structure.

Amlodipine besylate is a white crystalline powder with a molecularweight of 567.1, is slightly soluble in water, and sparingly soluble inethanol.

Amlodipine is commercially available as NORVASC® (amlodipine besylate)Tablets in strengths of tablets equivalent to 2.5, 5, and 10 mg ofamlodipine for oral administration. In addition to the amlodipinebesylate, each tablet contains the following inactive ingredients:microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodiumstarch glycolate, and magnesium stearate. The 10-mg dosage strength forNORVASC® is the reference listed drug (or reference product).

Amlodipine undergoes extensive metabolism and none of the metaboliteshave significant calcium antagonist activity relative to amlodipine.See, e.g., Stopher at S56. One of the amlodipine metabolites, known asAmlodipine Related Substance A (or “Impurity A” (alternatively referredto as Amlodipine Besylate EP Impurity D″ or “Dehydro Amlodipine”) havinga CAS No. of 113994-41-5), may form from amlodipine via oxidation of thepyridine ring. Ragno at 20. The chemical structure of Amlodipine RelatedSubstance A (viz., Impurity A) is shown below.

The Impurity A related substance does not show any significant calciumantagonist activity relative to amlodipine. Stopher at S59. Additionalamlodipine degradation impurities have been reported in the literature.See, e.g., Rapolu at 61 (reporting rearrangement products) and Murakamiat 75 (reporting Maillard reaction product between amlodipine and areducing disaccharide).

Amlodipine itself is not satisfactory in photostability and preservationstability, and various salts are formed to improve them. For example,Davison teaches that besylate salt and maleate salt are preferable fromamong various salts of amlodipine, including tosylate, succinate,salicylate, maleate, acetate, and hydrochloride.

Nahata reports the stability of amlodipine besylate in two suspensiondosage forms. Particularly, Nahata reported stabilities ofextemporaneous dosage forms prepared from crushed NORVASC® tablets intwo different vehicles. Based on the results presented therein, Nahatafound that the prepared amlodipine suspension dosage forms were stablefor 91 days under refrigerated conditions (4° C.) or 56 days at roomtemperature (25° C.).

Another salt form, amlodipine benzoate, is also commercially availablein the United States under the brand name KATERZIA® (amlodipine) oralsuspension. KATERZIA® contains 1.30 mg/mL amlodipine benzoate,equivalent to 1 mg/mL amlodipine, as well as the following inactiveingredients: citric acid, colloidal silicon dioxide, hypromellose,maltodextrin, polysorbate 80, simethicone, sodium benzoate, sodiumbesylate, sodium citrate, sodium hydroxide, sucralose, and water asinactive ingredients. See KATERZIA® Label; see also Brauer. KATERZIA® isa white to off-white oral suspension. The KATERZIA® PrescribingInformation states that KATERZIA® “should be stored refrigerated (2° C.to 8° C./36° F. to 46° F.). Avoid freezing and excessive heat. Protectfrom light.” Because KATERZIA® is a suspension product, the KATERZIA®Label states that the end user should shake before using.

Tatsumi describes an aqueous oral preparation (jelly preparation) ofamlodipine, which is reportedly stable and rapidly disintegrable. Theamlodipine stability may be improved by using an anionic surfactanthaving a sulfuric acid group or a sulfonic acid group (e.g., sodiumlauryl sulfate) as a stabilizer in an aqueous solution of amlodipine,preparing a liquid stable in the range of pH 5-7 as the liquid property,and adding and mixing a gelling agent, a fine powder solid and a gellingregulator.

Davison reports a sterile aqueous solution containing amlodipinebesylate for parenteral administration that includes 10 to 40% by volumeof propylene glycol and about 1% w/v of sodium chloride.

Noburu describes a solution of amlodipine besylate having propyleneglycol and a sugar alcohol as essential components, as well as water inan amount that ranges from 10% to 60% by weight. Stability tests (at 60°C. for 14-days) of compositions disclosed therein showed that amlodipinebesylate is incompatible with glycerin showing discoloration,precipitation, and an increased impurity level.

Mandal describes amlodipine liquid formulations containing glycerin,maltitol, butylated hydroxy toluene, a flavoring agent, water, andoptionally ethanol. The amount of water in the Mandal amlodipine liquidformulations is about 11% w/w. Results show that the Mandal formulationsprovide for unacceptable impurity levels. Results presented hereinprovide a basis for better understanding the unacceptable impuritylevels of Mandal's amlodipine formulations.

Presently, there is no commercial product of amlodipine available inliquid oral solution form. As stated above, amlodipine is available insolid tablet dosage form (Norvasc®). The currently marketed amlodipinetablet may be difficult to swallow by the pediatric and geriatricpopulations, as well as by patients with swallowing impediments andblockages and is in critical condition.

Also as stated above, amlodipine is available in a suspension dosageform (KATERZIA®), but KATERZIA® requires strict storage conditionsincluding refrigeration. One may appreciate that a suspension dosageform may be disadvantageous with respect to dose uniformity because ofsedimentation and poor dispersibility. The lack of dose uniformity mayresult in an incorrect dosage amount, and thus, may be problematic forthe treatment of a patient with hypertension and/or coronary arterydisease at least because a satisfactory therapeutic effect may not beachieved.

Despite a market demand for alternative oral formulations, there is nocommercially available amlodipine-containing oral solution dosage form.The oral solution dosage form addresses patients that have difficultyswallowing tablets. Further, an oral solution dosage form addressespotential problems associated with a suspension product because itprovides assurance of dosage uniformity upon administration to patientsand eliminates difficulty of administration.

While investigating amlodipine-containing oral solution dosage forms, itwas discovered that amlodipine stability depends on the inactiveingredients present in the formulation. The liquid formulationsdisclosed herein serve to solve the above-mentioned drawbacks of prioramlodipine-containing formulations.

SUMMARY

Disclosed herein is a liquid pharmaceutical formulation substantiallyfree of water, comprising: (i) amlodipine or a pharmaceuticallyacceptable salt thereof, (ii) at least one pharmaceutically acceptableexcipient, and (iii) a sufficient amount of a vehicle comprisingglycerin. Also disclosed herein is a liquid pharmaceutical formulationsubstantially free of water and ethanol, comprising: (i) amlodipine or apharmaceutically acceptable salt thereof, (ii) at least onepharmaceutically acceptable excipient, and (iii) a sufficient amount ofa vehicle comprising glycerin.

Definitions

As used herein, the singular forms “a,” “an,” and “the” include pluralreferences unless the context clearly dictates otherwise. Unless definedotherwise, all technical and scientific terms used herein have the samemeanings as commonly understood by one of ordinary skill in the art.

The expression “substantially free of water,” as used herein, refers toan amount of water less than or equal to about 5% w/w of the totalweight of the formulation, including about 4% w/w, about 3% w/w, about2% w/w, about 1% w/w, about 0.5% w/w, about 0.1% w/w, and about 0.01%w/w or lower (e.g., about 0% w/w of water).

The expression “substantially free of ethanol,” as used herein, refersto an amount of ethanol less than or equal to about 5% w/w of the totalweight of the formulation, including about 4% w/w, about 3% w/w, about2% w/w, about 1% w/w, about 0.5% w/w, about 0.1% w/w, and about 0.01%w/w or lower (e.g., about 0% w/w of ethanol).

The expression “% w/w,” as used herein, refers to the percent of theweight of an identified component based on the total weight of theformulation.

The expressions “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where the event occurs and instanceswhere it does not.

The expression “pharmaceutically acceptable,” as used herein refers toan excipient having compatibility with the other ingredients of theformulation and not deleterious to the recipient thereof.

DETAILED DESCRIPTION

Disclosed herein is a liquid pharmaceutical formulation substantiallyfree of water, comprising: (i) amlodipine or a pharmaceuticallyacceptable salt thereof, (ii) at least one pharmaceutically acceptableexcipient, and (iii) a sufficient amount of a vehicle comprisingglycerin.

As related to amlodipine or a pharmaceutically acceptable salt thereofand the at least one pharmaceutically acceptable excipient, the liquidpharmaceutical formulation is in the form of a solution.

In one aspect, the amount of amlodipine or a pharmaceutically acceptablesalt thereof, based on amlodipine, ranges from about 0.001% w/w to about0.5% w/w based on the total weight of the formulation, and all values inbetween, for example, about 0.002% w/w, about 0.003% w/w, about 0.004%w/w, about 0.005% w/w, about 0.006% w/w, about 0.007% w/w, about 0.008%w/w, about 0.009% w/w, about 0.01% w/w, about 0.02% w/w, about 0.03%w/w, about 0.04% w/w, about 0.05% w/w, about 0.06% w/w, about 0.07% w/w,about 0.08% w/w, about 0.09% w/w, about 0.10% w/w, about 0.11% w/w,about 0.12% w/w, about 0.13% w/w, about 0.14% w/w, about 0.15% w/w,about 0.16% w/w, about 0.17% w/w, about 0.18% w/w, about 0.19% w/w,about 0.20% w/w, about 0.21% w/w, about 0.22% w/w, about 0.23% w/w,about 0.24% w/w, about 0.25% w/w, about 0.26% w/w, about 0.27% w/w,about 0.28% w/w, about 0.29% w/w, about 0.30% w/w, about 0.31% w/w,about 0.32% w/w, about 0.33% w/w, about 0.34% w/w, about 0.35% w/w,about 0.36% w/w, about 0.37% w/w, about 0.38% w/w, about 0.39% w/w,about 0.40% w/w, about 0.41% w/w, about 0.42% w/w, about 0.43% w/w,about 0.44% w/w, about 0.45% w/w, about 0.46% w/w, about 0.47% w/w,about 0.48% w/w, and about 0.49% w/w.

In another aspect, the amount of amlodipine or a pharmaceuticallyacceptable salt thereof, based on amlodipine, ranges from about 0.005%w/w to about 0.15% w/w.

In yet another aspect, the amount of amlodipine or a pharmaceuticallyacceptable salt thereof, based on amlodipine, ranges from about 0.08%w/w to about 0.12% w/w.

Pharmaceutically acceptable salts of amlodipine include, but are notlimited to, amlodipine besylate, amlodipine maleate, amlodipinebenzoate, amlodipine tosylate, amlodipine succinate, amlodipinesalicylate, amlodipine acetate, and amlodipine hydrochloride, as well asother pharmaceutically acceptable salts described, for example, byBerge.

In one aspect, a pharmaceutically acceptable salt relates to amlodipinebesylate. For ease of reference, the reported molecular weight ofamlodipine besylate is 567.1 g/mol (“ABMW”), while the reportedmolecular weight of amlodipine is 408.879 g/mol (“AMW”). One may readilyconvert an amount of amlodipine besylate to an amount of amlodipine bymultiplying the amount of amlodipine besylate by a factor thatcorresponds to the ratio of the respective molecular weights ofamlodipine and amlodipine besylate (viz., AMW/ABMW=408.879/567.1≈0.72).

Liquid formulations disclosed herein result in an amlodipine stabilityheretofore not observed. For instance, a formulation disclosed hereinhas an amlodipine content of: (i) 100±10% amlodipine labeled contentwhen stored for about 24-months at 25±2° C. and 60±5% relative humidity;(ii) 100±10% amlodipine labeled content when stored for about 18-monthsat 25±2° C. and 60±5% relative humidity; (iii) 100±10% amlodipinelabeled content when stored for about 12-months at 25±2° C. and 60±5%relative humidity; (iv) 100±5% amlodipine labeled content when storedfor about 24-months at 25±2° C. and 60±5% relative humidity; (v) 100±5%amlodipine labeled content when stored for about 18-months at 25±2° C.and 60±5% relative humidity; (vi) 100±5% amlodipine labeled content whenstored for about 12-months at 25±2° C. and 60±5% relative humidity; (vi)100±5% amlodipine labeled content when stored for about 12-months at30±2° C. and 65±5% relative humidity; and/or (vii) 100±5% amlodipinelabeled content when stored for about 6-months at 40±2° C. and 75±5%relative humidity.

One may appreciate that the amlodipine labeled content refers to thestated amount of amlodipine present in the formulation. Thus, a liquidformulation that contains about 0.1% w/w amlodipine by weight of theformulation relates to the labeled content. Thus, 100±10% of labeledcontent of about 0.1% w/w corresponds to an amount of amlodipine ofabout 0.09% w/w to about 0.11% w/w (or 0.1±0.01% w/w).

In certain embodiments, it may be convenient to identify the amlodipinelabeled content in terms of a mass amount per unit volume, such as, forexample, 5 mg amlodipine per 5 mL of formulation or 1 mg amlodipine per1 mL of formulation. One may convert the amount of amlodipine expressedas a percent based on the total weight of the formulation (e.g.,amlodipine % w/w) by multiplying the amlodipine amount (in % w/w) by10-times the stated solution density. As an example, if the formulationcontains about 0.08% w/w amlodipine and the solution density is about1.25 g/mL, then the amount of amlodipine in the solution is about 1mg/mL. Thus, 100±10% of labeled content of about 1 mg amlodipine per 1mL of formulation corresponds to an amount of amlodipine of about 0.9mg/mL to about 1.1 mg/mL (or 1.0±0.1 mg/mL).

Liquid formulations disclosed herein result in a reduced amount ofAmlodipine Related Substance A (viz., Impurity A). For instance, aformulation disclosed herein has an amount of Impurity A of: (i) notmore than about 3% w/w when stored for about 24-months at 25±2° C. and60±5% relative humidity; (ii) not more than about 3% w/w when stored forabout 18-months at 25±2° C. and 60±5% relative humidity; (iii) not morethan about 3% w/w when stored for about 12-months at 25±2° C. and 60±5%relative humidity; (iv) not more than about 1% w/w when stored for about24-months at 25±2° C. and 60±5% relative humidity; (v) not more thanabout 1% w/w when stored for about 18-months at 25±2° C. and 60±5%relative humidity; (vi) not more than about 1% w/w when stored for about12-months at 25±2° C. and 60±5% relative humidity; (vi) not more thanabout 1% w/w when stored for about 12-months at 30±2° C. and 65±5%relative humidity; and/or (vii) not more than about 1% w/w when storedfor about 6-months at 40±2° C. and 75±5% relative humidity.

The liquid formulations disclosed herein comprise at least onepharmaceutically acceptable excipient, which may include a sweeteneragent, an antioxidant, a co-solvent, a flavoring agent, or a combinationthereof.

The amount of a sweetener agent, if present, ranges from about 0% w/w toabout 11% w/w, based on the total weight of the formulation, and allvalues in between, for example, about 0.1% w/w, about 0.2% w/w, about0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7%w/w, about 0.8% w/w, about 0.9% w/w, about 1.0% w/w, about 1.1% w/w,about 1.2% w/w, about 1.3% w/w, about 1.4% w/w, about 1.5% w/w, about1.6% w/w, about 1.7% w/w, about 1.8% w/w, about 1.9% w/w, about 2.0%w/w, about 2.1% w/w, about 2.2% w/w, about 2.3% w/w, about 2.4% w/w,about 2.5% w/w, about 2.6% w/w, about 2.7% w/w, about 2.8% w/w, about2.9% w/w, about 3.0% w/w, about 3.1% w/w, about 3.2% w/w, about 3.3%w/w, about 3.4% w/w, about 3.5% w/w, about 3.6% w/w, about 3.7% w/w,about 3.8% w/w, about 3.9% w/w, about 4.0% w/w, about 4.1% w/w, about4.2% w/w, about 4.3% w/w, about 4.4% w/w, about 4.5% w/w, about 4.6%w/w, about 4.7% w/w, about 4.8% w/w, about 4.9% w/w, about 5.0% w/w,about 5.1% w/w, about 5.2% w/w, about 5.3% w/w, about 5.4% w/w, about5.5% w/w, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9%w/w, about 6.0% w/w, about 6.1% w/w, about 6.2% w/w, about 6.3% w/w,about 6.4% w/w, about 6.5% w/w, about 6.6% w/w, about 6.7% w/w, about6.8% w/w, about 6.9% w/w, about 7.0% w/w, about 7.1% w/w, about 7.2%w/w, about 7.3% w/w, about 7.4% w/w, about 7.5% w/w, about 7.6% w/w,about 7.7% w/w, about 7.8% w/w, about 7.9% w/w, about 8.0% w/w, about8.1% w/w, about 8.2% w/w, about 8.3% w/w, about 8.4% w/w, about 8.5%w/w, about 8.6% w/w, about 8.7% w/w, about 8.8% w/w, about 8.9% w/w,about 9.0% w/w, about 9.1% w/w, about 9.2% w/w, about 9.3% w/w, about9.4% w/w, about 9.5% w/w, about 9.6% w/w, about 9.7% w/w, about 9.8%w/w, about 9.9% w/w, about 10.0% w/w, about 10.1% w/w, about 10.2% w/w,about 10.3% w/w, about 10.4% w/w, about 10.5% w/w, about 10.6% w/w,about 10.7% w/w, about 10.8% w/w, and about 10.9% w/w.

Examples of sweetener agents include, but are not limited to acesulfamepotassium, alitame, aspartame, compressible sugar, confectioner's sugar,dextrose, erythritol, fructose, glycerin, glycine, inulin, isomalt,lactitol, liquid glucose, maltitol, maltitol solution, a maltitololigomer, maltose, mannitol, neohesperidin dihydrochalcone, neotame,saccharin, saccharin sodium, sodium cyclamate, sorbitol, sucralose,sucrose, tagatose, thaumatin, trehalose, and xylitol.

In one aspect, the sweetener agent comprises maltitol. The Handbookexplains that maltitol may be commercially available as a solid (e.g.,Amalty; Maltbit, Maltisorb, among others) and as a liquid solution(e.g., Finmalt L, Lycasin HBC, Lycasin 80/55, among others). TheHandbook describes maltitol-containing compositions, including, forexample Lycasin® 80/55 (alternatively referred to herein as liquidmaltitol), which comprises a dried content of about 75% and a maltitolcontent of about 52% w/w, as well as a specific gravity of about 1.36 at20° C. See the Handbook at 416-417; see also Serpelloni and Dodd. Onemay appreciate that liquid maltitol contains a certain amount of water,e.g., 25% w/w. One may appreciate that solid maltitol may be used inplace of liquid maltitol.

In one aspect, the sweetener agent comprises maltitol in an amount offrom about 5.5% w/w to about 7.0% w/w, and all values in between, forexample, about 5.6% w/w, about 5.7% w/w, about 5.8% w/w, about 5.9% w/w,about 6.1% w/w, about 6.2% w/w, about 6.3% w/w, about 6.4% w/w, about6.5% w/w, about 6.6% w/w, about 6.7% w/w, about 6.8% w/w, and about 6.9%w/w.

In another aspect, the sweetener agent comprises glycyrrhizic acid,which is commercially available under the tradename Magnasweet®.Magnasweet® 110 contains from 8.5 to 10% w/w monoammoniumglycyrrhizinate, as measured by the content of glycyrrhizic acid, in avehicle comprising glycerin having a specific gravity of about 1.27 at20° C. A typical amount of monoammonium glycyrrhizinate, as measured bythe content of glycyrrhizic acid, found in Magnasweet® 110 is about 9.9%w/w.

An antioxidant, if present, ranges from about 0.01% w/w to about 0.1%w/w and all values in between, for example, about 0.02% w/w, about 0.03%w/w, about 0.04% w/w, about 0.05% w/w, about 0.06% w/w, about 0.07% w/w,about 0.08% w/w, and about 0.09% w/w.

Examples of antioxidants include, but are not limited to, ascorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,erythorbic acid, ethyl oleate, methionine, monothioglycerol, propylgallate, sodium ascorbate, thymol, tocopherol (e.g., alpha tocopherol),vitamin E, and vitamin E polyethylene glycol succinate.

In one aspect, the antioxidant comprises butylated hydroxyanisole in anamount of about 0.01% w/w to 0.1% w/w and all values in between. Inanother aspect, the antioxidant comprises butylated hydroxyanisole in anamount of about 0.03% w/w to about 0.04% w/w.

Examples of a co-solvent include, but are not limited to, an alcohol(e.g., ethanol), a glycol (e.g., propylene glycol, ethylene glycol, anda polyethylene glycol), and the like.

A co-solvent, if present, ranges from about 1 to about 15% w/w, based onthe total weight of the formulation, and all values in between, forexample, about 1.1% w/w, about 1.2% w/w, about 1.3% w/w, about 1.4% w/w,about 1.5% w/w, about 1.6% w/w, about 1.7% w/w, about 1.8% w/w, about1.9% w/w, about 2.0% w/w, about 2.1% w/w, about 2.2% w/w, about 2.3%w/w, about 2.4% w/w, about 2.5% w/w, about 2.6% w/w, about 2.7% w/w,about 2.8% w/w, about 2.9% w/w, about 3.0% w/w, about 3.1% w/w, about3.2% w/w, about 3.3% w/w, about 3.4% w/w, about 3.5% w/w, about 3.6%w/w, about 3.7% w/w, about 3.8% w/w, about 3.9% w/w, about 4.0% w/w,about 4.1% w/w, about 4.2% w/w, about 4.3% w/w, about 4.4% w/w, about4.5% w/w, about 4.6% w/w, about 4.7% w/w, about 4.8% w/w, about 4.9%w/w, about 5.0% w/w, about 5.1% w/w, about 5.2% w/w, about 5.3% w/w,about 5.4% w/w, about 5.5% w/w, about 5.6% w/w, about 5.7% w/w, about5.8% w/w, about 5.9% w/w, about 6.0% w/w, about 6.1% w/w, about 6.2%w/w, about 6.3% w/w, about 6.4% w/w, about 6.5% w/w, about 6.6% w/w,about 6.7% w/w, 6.8% w/w, about 6.9% w/w, about 7.0% w/w, about 7.1%w/w, about 7.2% w/w, about 7.3% w/w, about 7.4% w/w, about 7.5% w/w,about 7.6% w/w, about 7.7% w/w, about 7.8% w/w, about 7.9% w/w, about8.0% w/w, about 8.1% w/w, about 8.2% w/w, about 8.3% w/w, about 8.4%w/w, about 8.5% w/w, about 8.6% w/w, about 8.7% w/w, about 8.8% w/w,about 8.9% w/w, about 9.0% w/w, about 9.1% w/w, about 9.2% w/w, about9.3% w/w, about 9.4% w/w, about 9.5% w/w, about 9.6% w/w, about 9.7%w/w, about 9.8% w/w, about 9.9% w/w, about 10.0% w/w, about 10.1% w/w,about 10.2% w/w, about 10.3% w/w, about 10.4% w/w, about 10.5% w/w,about 10.6% w/w, about 10.7% w/w, about 10.8% w/w, about and 10.9% w/w,about 11.0% w/w, about 11.1% w/w, about 11.2% w/w, about 11.3% w/w,about 11.4% w/w, about 11.5% w/w, about 11.6% w/w, about 11.7% w/w,about 11.8% w/w, about 11.9% w/w, about 12.0% w/w, about 12.1% w/w,about 12.2% w/w, about 12.3% w/w, about 12.4% w/w, about 12.5% w/w,about 12.6% w/w, about 12.7% w/w, about 12.8% w/w, about 12.9% w/w,about 13.0% w/w, about 13.1% w/w, about 13.2% w/w, about 13.3% w/w,about 13.4% w/w, about 13.5% w/w, about 13.6% w/w, about 13.7% w/w,about 13.8% w/w, about 13.9% w/w, about 14.0% w/w, about 14.1% w/w,about 14.2% w/w, about 14.3% w/w, about 14.4% w/w, about 14.5% w/w,about 14.6% w/w, about 14.7% w/w, about 14.8% w/w, about and about 14.9%w/w.

Examples of flavoring agents include, but are not limited to, cherry,orange, banana, strawberry or other acceptable fruit flavors, ormixtures of cherry, orange, and other acceptable fruit flavors.Additional examples of flavoring agents include, but are not limited to,cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil,anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil ofsage, oil of bitter almonds, and cassia oil and the like or anycombinations thereof. Further examples of flavoring agents include, butare not limited to, vanilla, citrus oil, including lemon, orange, grape,lime and grapefruit, and fruit essences, including apple, banana, pear,peach, strawberry, raspberry, cherry, plums pineapple, apricot,peppermint, Tutti Frutti flavor, mixed berry, and so forth and the likeor any combinations thereof. Solid forms, such as spray dried forms offlavoring agents, may also be useful in the liquid dosage formsdisclosed herein.

A flavoring agent, if present, ranges from about 0.001 to about 0.020%w/w, based on the total weight of the formulation, and all values inbetween, for example, about 0.002% w/w, about 0.003% w/w, about 0.004%w/w, about 0.005% w/w, about 0.006% w/w, about 0.007% w/w, about 0.008%w/w, about 0.009% w/w, about 0.01% w/w, about 0.011% w/w, about 0.012%,about 0.013% w/w, about 0.014% w/w, about 0.015% w/w, about 0.016% w/w,about 0.017% w/w, about 0.018% w/w, and about 0.019% w/w.

The vehicle comprising glycerin may be present in a sufficient (viz.,Q.S.) amount to achieve a stated ingredient concentration, e.g.,amlodipine concentration. A sufficient amount of a vehicle comprisingglycerin includes for example, an amount of glycerin that ranges fromabout 73% w/w to about 99% w/w, and all values in between, for example,about 74% w/w, about 75% w/w, about 76% w/w, about 77% w/w, about 78%w/w, about 79% w/w, about 80% w/w, about 81% w/w, about 82% w/w, about83% w/w, about 84% w/w, about 85% w/w, about 86% w/w, about 87% w/w,about 88% w/w, about 89% w/w, about 90% w/w, about 91% w/w, about 92%w/w, about 93% w/w, about 94% w/w, about 95% w/w, about 96% w/w, about97% w/w, and about 98% w/w.

In one aspect related to the vehicle comprising glycerin, the glycerinmay be present in an amount selected from the group consisting of about77% w/w, about 84% w/w, about 85% w/w, and about 86% w/w.

One aspect relates to a liquid pharmaceutical formulation substantiallyfree of water, comprising: about 0.07 to about 0.2% w/w of amlodipinebesylate; about 4% w/w to about 7% w/w of a sweetening agent; about0.01% to about 0.05% w/w of an antioxidant; optionally about 0.006% w/wto about 0.010% w/w of a flavoring agent; optionally about 2% w/w toabout 4% w/w ethanol; and a sufficient amount of a vehicle comprisingglycerin.

Another aspect relates to a liquid pharmaceutical formulationsubstantially free of water, comprising: about 0.08 to about 0.14% w/wof amlodipine besylate; about 4% w/w to about 7% w/w of a sweeteningagent; about 0.01% to about 0.05% w/w of an antioxidant; optionallyabout 0.006% w/w to about 0.010% w/w of a flavoring agent; optionallyabout 2% w/w to about 4% w/w ethanol; and a sufficient amount of avehicle comprising glycerin.

Yet another aspect relates to a liquid pharmaceutical formulationsubstantially free of water, comprising: about 0.10 to about 0.12% w/wof amlodipine besylate; about 4% w/w to about 7% w/w of a sweeteningagent; about 0.01% to about 0.05% w/w of an antioxidant; optionallyabout 0.006% w/w to about 0.010% w/w of a flavoring agent; optionallyabout 2% w/w to about 4% w/w ethanol; and a sufficient amount of avehicle comprising glycerin.

Another aspect relates to a liquid pharmaceutical formulationsubstantially free of water, comprising: about 0.10 to about 0.12% w/wof amlodipine besylate; about 4% w/w to about 7% w/w of a sweeteningagent; about 0.03% to about 0.04% w/w of an antioxidant; optionallyabout 0.006% w/w to about 0.010% w/w of a flavoring agent; optionallyabout 2% w/w to about 4% w/w ethanol; and a sufficient amount of avehicle comprising glycerin.

And yet another aspect relates to a liquid pharmaceutical formulationsubstantially free of water, comprising: about 0.11% w/w of amlodipinebesylate; about 4% w/w to about 7% w/w of a sweetening agent; about0.01% to about 0.05% w/w of an antioxidant; optionally about 0.006% w/wto about 0.010% w/w of a flavoring agent; optionally about 2% w/w toabout 4% w/w ethanol; and a sufficient amount of a vehicle comprisingglycerin.

And yet another aspect relates to a liquid pharmaceutical formulationsubstantially free of water, comprising: about 0.11% w/w of amlodipinebesylate; about 4% w/w to about 7% w/w of a sweetening agent comprisingmaltitol; about 0.01% to about 0.05% w/w of an antioxidant comprisingbutylated hydroxyanisole; optionally about 0.006% w/w to about 0.010%w/w of a flavoring agent; optionally about 2% w/w to about 4% w/wethanol; and a sufficient amount of a vehicle comprising glycerin.

A further aspect relates to a liquid pharmaceutical formulationsubstantially free of water, comprising: about 0.11% w/w of amlodipinebesylate; about 5% w/w to about 7% w/w of a sweetening agent comprisingmaltitol; about 0.03% w/w of an antioxidant comprising butylatedhydroxyanisole; optionally about 0.008% w/w to about 0.010% w/w of aflavoring agent; optionally about 2% w/w to about 4% w/w ethanol; and asufficient amount of a vehicle comprising glycerin.

An additional aspect relates to a liquid pharmaceutical formulationsubstantially free of water, comprising: about 0.08% w/w of amlodipine;as its besylate salt; about 5% w/w to about 7% w/w of a sweetening agentcomprising maltitol; about 0.03% w/w of an antioxidant comprisingbutylated hydroxyanisole; optionally about 0.008% w/w to about 0.010%w/w of a flavoring agent; about 2.5% w/w ethanol; and a sufficientamount of a vehicle comprising glycerin.

An additional aspect relates to a liquid pharmaceutical formulationsubstantially free of water, comprising: about 0.08% w/w of amlodipine;as its besylate salt; about 6% w/w of a sweetening agent comprisingmaltitol; about 0.03% w/w of an antioxidant comprising butylatedhydroxyanisole; about 0.008% w/w to about 0.010% w/w of a flavoringagent; about 2.5% w/w ethanol; and a sufficient amount of a vehiclecomprising glycerin.

An additional aspect relates to a liquid pharmaceutical formulationsubstantially free of water, comprising: about 0.08% w/w of amlodipine;as its besylate salt; about 11% w/w of a liquid maltitol syrupcomprising maltitol; about 0.03% w/w of an antioxidant comprisingbutylated hydroxyanisole; about 0.008% w/w to about 0.010% w/w of aflavoring agent; about 2.5% w/w ethanol; and a vehicle comprising about86% w/w amount of glycerin.

In an alternative embodiment, it may be desirable to reduce the amountof water and ethanol in a formulation.

Accordingly, disclosed herein is a liquid pharmaceutical formulationsubstantially free of water and ethanol, comprising: (i) amlodipine or apharmaceutically acceptable salt thereof, (ii) at least onepharmaceutically acceptable excipient, and (iii) a sufficient amount ofa vehicle comprising glycerin.

One aspect relates to a liquid pharmaceutical formulation substantiallyfree of water and ethanol, comprising: about 0.05% w/w to about 0.15%w/w of amlodipine besylate; about 0.01% to about 0.07% w/w of anantioxidant; about 0.005% w/w to about 0.015% w/w of a flavoring agent;about 4% w/w to about 10% w/w of a glycol; and a sufficient amount of avehicle comprising glycerin.

Yet another aspect relates to a liquid pharmaceutical formulationsubstantially free of water and ethanol, comprising: about 0.07% w/w toabout 0.13% w/w of amlodipine besylate; about 0.02% w/w to about 0.06%w/w of an antioxidant; about 0.007% w/w to about 0.013% w/w of aflavoring agent; about 5% w/w to about 9% w/w of a glycol; and asufficient amount of a vehicle comprising glycerin.

And yet another aspect relates to a liquid pharmaceutical formulationsubstantially free of water and ethanol, comprising: about 0.08% w/w toabout 0.12% w/w of amlodipine besylate; about 0.03% w/w to about 0.05%w/w of an antioxidant; about 0.009% w/w to about 0.011% w/w of aflavoring agent; about 6% w/w to about 8% w/w of a glycol comprisingpropylene glycol; and a sufficient amount of a vehicle comprisingglycerin.

Another aspect relates to a liquid pharmaceutical formulationsubstantially free of water and ethanol, comprising: about 0.09% w/w toabout 0.11% w/w of amlodipine besylate; about 0.04% w/w of anantioxidant comprising butylated hydroxyanisole; about 0.01% w/w of aflavoring agent; about 7% w/w of a glycol comprising propylene glycol;and a sufficient amount of a vehicle comprising glycerin.

And yet another aspect relates to a liquid pharmaceutical formulationsubstantially free of water and ethanol, comprising: about 0.10% w/w ofamlodipine besylate; about 0.04% w/w of an antioxidant comprisingbutylated hydroxyanisole; about 0.01% w/w of a flavoring agent; about 7%w/w of propylene glycol; and a vehicle comprising about 91% w/w to about93% w/w of a glycerin.

The liquid formulation substantially free of water and ethanol resultsin an amlodipine stability heretofore not observed. For instance, theliquid formulation substantially free of water and ethanol has anamlodipine content of: (i) 100±10% labeled content when stored for about24-months at 25±2° C. and 60±5% relative humidity; (ii) 100±10% labeledcontent when stored for about 18-months at 25±2° C. and 60±5% relativehumidity; (iii) 100±10% labeled content when stored for about 12-monthsat 25±2° C. and 60±5% relative humidity; (iv) 100±5% labeled contentwhen stored for about 24-months at 25±2° C. and 60±5% relative humidity;(v) 100±5% labeled content when stored for about 18-months at 25±2° C.and 60±5% relative humidity; (vi) 100±5% labeled content when stored forabout 12-months at 25±2° C. and 60±5% relative humidity; (vi) 100±5%labeled content when stored for about 12-months at 30±2° C. and 65±5%relative humidity; and/or (vii) 100±5% labeled content when stored forabout 6-months at 40±2° C. and 75±5% relative humidity.

The liquid formulation substantially free of water and ethanol resultsin an amlodipine stability heretofore not observed. For instance, theliquid formulation substantially free of water and ethanol has an amountof Impurity A of: (i) not more than about 3% w/w when stored for about24-months at 25±2° C. and 60±5% relative humidity; (ii) not more thanabout 3% w/w when stored for about 18-months at 25±2° C. and 60±5%relative humidity; (iii) not more than about 3% w/w when stored forabout 12-months at 25±2° C. and 60±5% relative humidity; (iv) not morethan about 1% w/w when stored for about 24-months at 25±2° C. and 60±5%relative humidity; (v) not more than about 1% w/w when stored for about18-months at 25±2° C. and 60±5% relative humidity; (vi) not more thanabout 1% w/w when stored for about 12-months at 25±2° C. and 60±5%relative humidity; (vi) not more than about 1% w/w when stored for about12-months at 30±2° C. and 65±5% relative humidity; and/or (vii) not morethan about 1% w/w when stored for about 6-months at 40±2° C. and 75±5%relative humidity.

The formulations described herein may be stored in a pharmaceuticallyacceptable closure system, such as, for example, an amber PET bottle oran amber glass bottle. The bottle volume is, for example, about 150 mLto about 200 mL, e.g., 185 mL, with a formulation volume of about 150mL. An amber colored bottle has a light transmission of, for example,less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%at any wavelength between 290 nm and 450 nm.

One aspect relates to a bottled product comprising a formulationdescribed herein. In one aspect, the bottled product comprises an amberglass bottle (see DMF No. 14003) with a pharmaceutically acceptableclosure (such as a 28 mm Polypropylene TE-CRC cap with EPE liner, seeDMF No. 18371).

Another aspect relates to a container comprising written material and abottle comprising any one of the formulations disclosed herein. Thewritten material includes, among other things, a description of theformulation and indications for use of the formulation, as summarizedbelow.

Indications

The formulations disclosed herein may be used for the treatment ofhypertension in adults and children 6 years and older. See the NORVASC®and KATERZIA® Labels. Additionally, the formulations disclosed hereinalso may be used in combination with other antihypertensive agents.

Examples of other antihypertensive agents include, but are not limitedto a loop diuretic, e.g., bumetanide, ethacrynic acid, furosemide,torsemide; a thiazide diuretic, e.g., epitizide, hydrochlorothiazide,chlorothiazide, bendroflumethiazide, methyclothiazide, polythiazide; athiazide-like diuretics, e.g., indapamide, chlorthalidone, metalozone,xipamide, clopamide, a potassium-sparing diuretic, e.g., amiloride,triamterene, spironolactone, eplerenone; an ACE inhibitor, e.g.,captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril,quinapril, ramipril, trandolapril, benazepril; an angiotensin IIreceptor antagonist, e.g., azilsartan, candesartan, eprosartan,irbesartan, losartan, olmesartan, telmisartan, valsartan, fimasartan; anadrenergic receptor antagonists, e.g., a beta blockers, e.g.,acebutolol, atenolol, bisoprolol, betaxolol, carteolol, carvedilol,labetalol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol,pindolol, propranolol, timolol; an alpha blocker, e.g., doxazosin,phentolamine, indoramin, phenoxybenzamine, prazosin, terazosin,tolazoline, a mixed alpha+beta blockers, e.g., bucindolol, carvedilol,labetalol, among others.

The formulations disclosed herein further may be used for either thesymptomatic treatment of chronic stable angina the treatment ofconfirmed or suspected vasospastic angina consistent with the NORVASC®and KATERZIA® Labels. Additionally, the formulations disclosed hereinalso may be used in combination with other antianginal agents.

Examples of antianginal agents include, but are not limited to nitratese.g., isosorbide dinitrate, isosorbide mononitrate, and nitroglycerin; acalcium antagonist e.g., diltiazem, nifedipine, nimodipine, andverapamil; a beta blockers, e.g., atenolol, pindolol, propranolol, andmetoprolol; ranolazine; among others.

The formulations disclosed herein further may be used for the treatmentof confirmed or suspected vasospastic angina.

In view of the foregoing, an aspect disclosed herein relates to a methodfor the treatment of hypertension in a patient in need thereof, whichcomprises administering to said patient a therapeutically effectiveamount of any one of the formulations disclosed herein. With respect tothis indication, and other indications contemplated herein, the patientmay be an adult patient (including a geriatric patient) and the patientmay be a pediatric patient.

Generally, the expression “therapeutically effective amount” refers toan amount of amlodipine sufficient to treat any one of the conditionsdisclosed herein.

As related to the treatment of hypertension, a therapeutically effectiveamount refers to the patient population in question. For instance, theusual initial antihypertensive oral dose of amlodipine is 5 mg orallyonce daily, and the maximum dose is 10 mg once daily. Alternatively, forsmall, fragile, or elderly patients, or patients with hepaticinsufficiency the amlodipine dose may be started on 2.5 mg once dailyand this dose may be used when adding the amlodipine formulationdisclosed herein in combination with another antihypertensive therapy.

Another aspect disclosed herein relates to a method for the treatment ofhypertension in a patient in need thereof, which comprises administeringto said patient a therapeutically effective amount of any one of theformulations disclosed herein in combination with an antihypertensiveagent. An effective antihypertensive oral dose in a pediatric patient(ages 6 to 17 years) is 2.5 to 5 mg once daily.

Another aspect disclosed herein relates to a method for the symptomatictreatment of a chronic stable angina in a patient in need thereof, whichcomprises administering to said patient a therapeutically effectiveamount of any one of the formulations disclosed herein.

Yet another aspect disclosed herein relates to a method for thetreatment of confirmed or suspected vasospastic angina in a patient inneed thereof, which comprises administering to said patient atherapeutically effective amount of any one of the formulationsdisclosed herein.

For either one of these two conditions (viz., symptomatic treatment of achronic stable angina and of confirmed or suspected vasospastic angina),a therapeutically effective corresponds to an amlodipine dose of 5 to 10mg once daily, with the lower dose suggested in the elderly and inpatients with hepatic insufficiency. Most patients will require 10 mgonce daily for adequate effect.

In some instances, the formulations disclosed herein may be useful forthe treatment of a coronary artery disease (CAD). Accordingly, anotheraspect relates to a method for the treatment a coronary artery diseasein a patient in need thereof, which comprises administering to saidpatient a therapeutically effective amount of any one of theformulations disclosed herein. In a patient with recently documented CADby angiography and without heart failure or an ejection fraction <40%,administration of an amlodipine-containing formulation disclosed hereinis indicated to reduce the risk of hospitalization for angina and toreduce the risk of a coronary revascularization procedure. Therecommended dose range for patients with coronary artery disease is 5 to10 mg once daily.

In some instances, the formulations disclosed herein may be useful forthe treatment of angina and/or high blood pressure when administered incombination with a therapeutically effective amount of a statin.Examples of statins include, but are not limited to atorvastatin,fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, andsimvastatin.

Processes for Preparation

In another embodiment, the formulation disclosed herein may be preparedby the process comprising the steps of:

-   a) adding a suitable amount of a vehicle comprising glycerin in a    first vessel;-   b) adding a suitable amount of a co-solvent in a second vessel;-   c) adding a suitable amount of antioxidant to the second vessel of    step b);-   d) adding a suitable amount of amlodipine besylate to the second    vessel of step c);-   e) adding a suitable amount of a vehicle comprising glycerin to the    second vessel of step d);-   f) transferring the contents of the second vessel of step d) to the    first vessel of step a);-   g) optionally adding a sweetener to the first vessel of step f);-   h) optionally adding a flavoring agent to the first vessel of step    g); and-   g) adding a remaining quantity of a vehicle comprising glycerin to    make up the volume.

Additional processes for preparing the formulations disclosed herein aredescribed in greater detail below.

Bioequivalence

One aspect relates to a liquid pharmaceutical formulation substantiallyfree of water or substantially free of water and ethanol, comprising:(i) amlodipine or a pharmaceutically acceptable salt thereof, (ii) atleast one pharmaceutically acceptable excipient, and (iii) a sufficientamount of a vehicle comprising glycerin; wherein administration of adose to a subject comprising 10 mg of amlodipine exhibits at least oneof the following characteristics: (a) a 90% Confidence Interval for theratio of the mean AUC (0-72 h) which is between 80% and 125%; (b) a 90%Confidence Interval for the ratio of the mean Cmax, which is between 80%and 125%; wherein the ratio of the mean refers to an observable (viz.,AUC (0-72 h) and/or Cmax) of the liquid formulation vs. the referencelisted drug (e.g., NORVASC® (amlodipine besylate, 10 mg, tablet) fororal administration).

In one aspect, the liquid formulation comprises about 0.08% w/w ofamlodipine; as its besylate salt; about 11% w/w of a liquid maltitolsyrup comprising maltitol; about 0.03% w/w of an antioxidant comprisingbutylated hydroxyanisole; about 0.008% w/w to about 0.010% w/w of aflavoring agent; about 2.5% w/w ethanol; and a vehicle comprising about86% w/w amount of glycerin; wherein upon administration of about 10 mLof formulation to a subject and separately the NORVASC® reference listeddrug to the subject results in a 90% confidence interval of anln-transformed geometric least squares mean for each of AUC (0-72 h) andCmax that ranges from about 80% to about 125%.

In one aspect, the liquid formulation comprises about 0.08% w/w ofamlodipine; as its besylate salt; about 11% w/w of a liquid maltitolsyrup comprising maltitol; about 0.03% w/w of an antioxidant comprisingbutylated hydroxyanisole; about 0.008% w/w to about 0.010% w/w of aflavoring agent; about 2.5% w/w ethanol; and about 86% w/w amount of avehicle comprising glycerin; wherein the liquid formulation isbioequivalent to the NORVASC® reference listed drug.

Formulation Development Work

As stated above, Mandal describes amlodipine liquid formulationscontaining glycerin, maltitol, butylated hydroxy toluene, a flavoringagent, water, and optionally ethanol. Also as stated above, results showthat the Mandal formulations provide for unacceptable impurity levels.Results presented herein provide a basis for better understanding theunacceptable impurity levels of Mandal's amlodipine formulations.

Amounts of amlodipine and other components identified here weredetermined chromatographically, e.g., HPLC or GC.

The Assay of Amlodipine was determined using a high performance liquidchromatographic system (HPLC) equipped with a Waters Spherisorb ODS-2(250×4.6) mm, 5 μm column and a Ultraviolet (UV, 237 nm) or diode array(PDA) detector, with a flow rate of 1.5 mL/min, an injection volume of10 μL, a column oven temperature of 35° C., and an autosamplertemperature of 25° C., a run time of 15 minutes, using a mobile phasecomprised of Solution A and Solution B in the ratio of 30:70% v/v,respectively. Solution A comprised of an acetate buffer, while SolutionB comprises acetonitrile. The acetate buffer was obtained by: (i)accurately weighing and transferring about 2.3 g of ammonium acetateinto 1000 mL of water and mix; (ii) adding 1 mL of triethylamine intothe solution of step (i) and mixing well; (iii) adjusting the pH ofsolution of step (ii) to 6.0±0.05 with diluted acetic acid; and (iv)filtering the solution of step (iii) through a 0.45 μm nylon membranefilter.

An amlodipine besylate standard (reference and working “AS”) wasprepared by: (i) accurately weighing and transferring about 70.0 mg ofamlodipine besylate (reference/working) standard into a 100-mLvolumetric flask, (ii) adding about 60 ml of diluent and sonicate todissolve (diluent comprised of methanol and water in a ratio of 70:30%v/v, respectively); (iii) filling 100-mL volumetric flask to the markwith diluent and mixing well; (iv) pipetting out 5.0 mL of solution ofstep (iii) into a 25-mL volumetric flask, and (v) filling 25-mLvolumetric flask to the mark with diluent and mixing well.

An amlodipine besylate sample (“AT”) was prepared by: (i) accuratelytransferring 5.0 mL sample solution (e.g., a formulation describedherein) into a 50.0 mL-volumetric flask; (ii) adding about 30.0 mL ofdiluent and sonicating for 5 minutes with intermittent shaking; (iii)filling the 50.0-mL volumetric flask to the mark with diluent and mixingwell; and (iv) filtering the solution of step (iii) through 0.45 μm PVDFfilter by discarding first 5 mL of filtrate.

Samples analyzed by HPLC, as described above, were used to calculate the% assay of amlodipine using the following formula.

${\%\mspace{14mu}{Assay}\mspace{14mu}{of}\mspace{14mu}{Amlodipine}} = {\left( \frac{AT}{AS} \right) \times \left( \frac{WS}{DS} \right) \times \left( \frac{DT}{WT} \right) \times \left( \frac{\left( \frac{Wt}{mL} \right)}{LC} \right) \times \left( \frac{409.0}{567.1} \right) \times P}$where

AT : Mean peak area of Amlodipine obtained from sample preparation AS :Mean peak area of Amlodipine obtained from standard preparation WS :Weight of Amlodipine besylate reference/working standard taken in mg DS: Dilution in standard preparation DT : Dilution in sample preparationWT : Weight of sample taken in mg Wt/ml : Weight per milliliter ofsample in mg/ml LC : Label claim in mg/ml 409.0 : Molecular weight ofAmlodipine 567.1 : Molecular weight of Amlodipine besylate P : Potencyof Amlodipine besylate reference/working standard

Assay amounts of butylhydroxy anisole, as well as ethanol, weredetermined in a similar manner as explained above, with perhaps changesin mobile phases, diluents, and instrumentation (e.g., gaschromatography for ethanol). Likewise, percent amounts of impurities(e.g., Impurity A), were determined in a similar manner as explainedabove, except that the % impurity was calculated from the followingexpression:

${\%\mspace{14mu}{Impurity}} = {\left( \frac{AT}{AS} \right) \times \left( \frac{WS}{DS} \right) \times \left( \frac{DT}{WT} \right) \times \left( \frac{\left( \frac{Wt}{mL} \right)}{LC} \right) \times \left( \frac{409.0}{567.1} \right) \times \left( \frac{1}{R\; R\; F} \right) \times P}$where the variables are identified above, and RRF refers to the relativeresponse factor. As a point of reference, the RRF-values for Amlodipineand Impurity A were 1.00 and 0.32, respectively. Additional parametersobserved include retention time (min) of 47 (AML) and 31 (Imp. A).Effect of Antioxidant on Liquid Solution of Amlodipine

Experiments were carried out to evaluate the effect of antioxidant onthe stability of the liquid solution of amlodipine. Two batches wereprepared: (i) Formulation A is with BHA as antioxidant and (ii)Formulation B is with BHT as antioxidant as mentioned in Table 1.

TABLE 1 Compositional makeup of Formulations A and B Formulation ID:Form. A Form. B (4 L) (4 L) Ingredients Quantity (mg)/mL Quantity(mg)/mL Amlodipine Besylate 1.385† 1.385† Glycerin 1000.0 1000.0 LiquidMaltitol 140.0 140.0 BHT 0.40 — BHA — 0.40 Ethanol absolute* 31.6‡ 31.6‡Purified water Qs to 1 mL Qs to 1 mL Abbreviations: BHT (butylatedhydroxytoluene) and BHA (butylated hydroxyanisole) †Equivalent to 1.00mg/mL amlodipine. ‡Corresponds to about 0.04 ml based on ethanol densityof 0.790 g/mL. Formulation density: 1.25 g/mL.

An exemplary process for preparing batches of Formulation A andFormulation B containing the above-mentioned ingredients is as follows.

1. Tare weight of SS manufacturing vessel S1: Add 98% of total batchsize 3.92 Kg of glycerin to SS manufacturing vessel S1.

2. Tare weight of SS manufacturing vessel S2: Add about 127 g of ethanolabsolute from total batch size in SS manufacturing vessel S2.

3. Add dispensed quantity of either BHT (about 1.6 g) or BHA (about 1.6g) in manufacturing vessel S2 step 2, stir well until clear solution isobtained.

4. Add dispensed quantity of amlodipine besylate (about 5.540 g) inmanufacturing vessel S2 step 3, stir well until hazy dispersion isobtained.

5. Add 80.0 gm of glycerin in manufacturing vessel S2, stir well untilclear solution is obtained.

6. Transfer the content of SS manufacturing vessel S2 of step 5, tovessel S1 of step 1. Stir well until clear homogeneous solution isobtained.

7. Add dispensed quantity of Lycasin 80/55 (about 560 g corresponding toabout 448 g of maltitol and about 112 g water) in manufacturing vesselS1 step 6, stir well until clear solution is obtained.

8. Add remaining quantity of purified water (about 227 g) to make up thevolume 4 L (about 5040 g) and stirred by overhead stirrer in SSmanufacturing vessel S1.

9. Filter the solution using 40-μm PP filter and filled in 150 mL Amberglass bottle with 28 mm CR cap.

N.B. The formulations identified above contain about 9% w/w of water.

Stability Study

The stability of Formulation A and Formulation B was evaluated bystoring samples at 40±2° C. and 75%±5% RH for 3 months. Table 2 belowsummarizes the observed Assay values for each of amlodipine besylate(“AB”), butylated hydroxy toluene (“BHT Assay”), and butylated hydroxyanisole (“BHA Assay”) with respect to labeled content, as well as theobserved values for Impurity A, Single maximum unknown impurity(“SMUI”), and Total Impurities (“Tot. Imps.”).

TABLE 2 Stability Results of Formulations A and B Form. A Form. BParameters Specification Initial 3M Initial 3M Description A clearUnclear Unclear A clear A clear pale straw off off pale straw pale strawcolored, white, white, colored, colored, viscous viscous viscous viscousviscous liquid. liquid. liquid, liquid liquid AB Assay NLT 90% and 98.3%94.9% 98.4% 95.3% NMT 110% of 1.385 mg/mL BHT Assay NLT 80% and 83.4%22.5% — — NMT 110% of 0.4 mg/mL BHA Assay NLT 80% and — — 99.4% 91.9%NMT 110% of 0.4 mg/mL Ethanol NLT 90% and 94.8% 90.1% 96.1% 92.2%content NMT 110% of 31.6 mg/mL Organic impurities (By HPLC) Impurity-ANMT 3.0% 0.06% 1.60% 0.07% 1.50% SMUT NMT 0.2% 0.02% 0.23% ND 0.11% Tot.Imps. NMT 3.5% 0.16% 2.19% 0.07% 1.87%

After 3-month stability study under the stated conditions, it wasobserved that the composition containing BHT 0.4 mg/ml (Form. A) showeda higher level of single maximum unknown impurity as compared to thecomposition containing BHA 0.4 mg/mL (Form. B). Additionally, the BHTcontent decreased significantly (viz., 83.4% of labelled content vs.22.5% of labelled content) after a three-month period. It was observedthat when solution contains BHT, the total impurities, including maximumunknown impurity increased even at 3 months storage while thecomposition containing BHA showed a reduced amount of total impurities.The data suggests a difference in the formulation stability whenantioxidant is changed from BHT to BHA. It should be noted that bothFormulation A and Formulation B had an added water content of about 9%w/w.

As stated above, Mandal describes amlodipine liquid formulationscontaining glycerin, maltitol, butylated hydroxy toluene (BHT), aflavoring agent, water, and optionally ethanol. The amount of water inthe Mandal amlodipine liquid formulations is about 11% w/w. Based on thedata presented herein, it may be reasonable to conclude that theunacceptable impurity levels observed for Mandal's formulations may bedue to the observed incompatibility of BHT and/or amlodipine in thepresence of water. As water may be a culprit associated with reducedstability, an additional investigation considered evaluating thestability of amlodipine liquid formulations in the presence of water.

Effect of Water on Stability of Liquid Solution of Amlodipine

Experiments were carried out to evaluate the effect of purified water onthe stability of the liquid solution of amlodipine. Two batches(Formulation C and Formulation D) were prepared—one with added water(Form. C) and the other without added water (Form. D), as shown in Table3.

TABLE 3 Compositional makeup of Formulations C and D Formulation ID:Form. C Form. D (4 L) (4 L) Ingredients Quantity (mg)/mL Quantity(mg)/mL Amlodipine Besylate 1.385† 1.385† Glycerin 1000.0 1000.0 LiquidMaltitol 140.0 140.0 BHA 0.40 0.40 Ethanol absolute 31.6‡ 31.6‡ Purifiedwater Qs to 1 mL — Water Content (% w/w) ≈9 ≈3 Abbreviation: BHA(butylated hydroxyanisole). †Equivalent to about 1 mg/mL amlodipine.‡Corresponds to about 0.04 mL based on ethanol density of 0.790 g/mL.Formulation density: 1.25 g/mL.

An exemplary process for preparing batches of Formulation C andFormulation D containing the above-mentioned ingredients is as follows.

1. Tare weight of SS manufacturing vessel S1: Add 98% of total batchsize 3.92 kg of glycerin SS manufacturing vessel S1.

2. Tare weight of SS manufacturing vessel S2: Add 127 gm of ethanolabsolute from total batch size in SS manufacturing vessel S2.

3. Add dispensed quantity of about 1.60 g of butylated hydroxyanisole inmanufacturing vessel S2 step 2, stir well until clear solution isobtained.

4. Add dispensed quantity of about 5.54 g of amlodipine besylate inmanufacturing vessel S2 step 3, stir well until hazy dispersion isobtained.

5. Add about 80.0 gm of glycerin in manufacturing vessel S2, stir welluntil clear solution is obtained.

6. Transfer the content of SS manufacturing vessel S2 of step 5, tovessel S1 of step 1. Stir well until clear homogeneous solution isobtained.

7. Add dispensed quantity of about 560 g of Lycasin 80/55 inmanufacturing vessel S1 step 6, stir well until clear solution isobtained.

8a. For Formulation C, add remaining quantity of purified water to makeup the volume 4 L=5 kg and stirred by overhead stirrer in SSmanufacturing vessel S1.

8b. For Formulation D, add remaining quantity of glycerin to make up thevolume 4 L=5 kg and stirred by overhead stirrer in SS manufacturingvessel S1.

9. Filter the solution using 40 μPP filter and filled in 150 mL Amberglass bottle with 28 mm CR cap.

Stability Study

The stability of Formulation C and Formulation D were evaluated bystoring samples at 40±2° C. and 75%±5% RH for 3 months. The table belowsummarizes the observed Assay values for amlodipine besylate (“ABAssay”) and butylated hydroxy anisole (“BHA Assay”) with respect tolabeled content, as well as the observed values for Impurity A, Singlemaximum unknown impurity (“SMUI”), and Total Impurities (“Tot. Imps.”).

TABLE 4 Stability Results of Formulations C and D Form. C Form. DParameters Specification Initial 3 M Initial 3 M AB Assay NLT 90%  98.4%95.3% 97.3% 97.3% and NMT 110% of 1.385 mg/mL Impurity-A NMT 3.0% 0.07%1.50% 0.05% 0.58% SMUT NMT 0.2% ND 0.11% 0.01% 0.07% Tot. Imps. NMT 3.5%0.07% 1.87% 0.07% 0.77%

The data plainly shows that Formulation C (containing added water)showed increased degradation, with respect to an increased amount ofImpurity A, as compared to the formulation without purified water(Formulation D). As stated above, the water content in Formulation C isabout 9% w/w, while the water content in Formulation D is about 2% w/w.These data show that the presence of added water contributes to thedegradation of amlodipine composition in liquid form. Given the factthat the liquid formulations exhibit any long term stability issurprising in view of the fact that Noburu plainly states thatamlodipine besylate is incompatible with glycerin.

Effect of Antioxidant Concentration on Liquid Solution of Amlodipine

Experiments were carried out to evaluate the effect of antioxidantamount on the stability of the liquid solution of amlodipine. Threebatches were prepared with differing amounts of BHA and with no addedBHA, as shown in Table 5.

TABLE 5 Compositional makeup of Formulations E-H Formulation ID: Form. EForm. F Form. G Form. H Batch size: 1 L 1 L 1 L 4 L Quantity QuantityQuantity Quantity Ingredients (mg)/mL (mg)/mL (mg)/mL (mg)/mL Amlodipine1.385† 1.385† 1.385† 1.385† Besylate Liquid 140.0 140.0 140.0 MaltitolBHA — 0.10 0.20 0.40 Ethanol 31.6‡ 31.6‡ absolute* Frozen 0.10 0.10 0.100.10 peppermint flavor Glycerin Qs to 1 mL Qs to 1 mL Abbreviation: BHA(butylated hydroxyanisole) †Equivalent to about 1 mg/mL amlodipine.‡Corresponds to about 0.04 mL based on ethanol density of 0.790 g/mL.Formulation density of about 1.25 g/mL.

An exemplary process for preparing batches of Formulations E, F, G, andH containing the above-mentioned ingredients is as follows.

1. Tare weight of SS manufacturing vessel S1: Add 98% of total batchsize of glycerin SS manufacturing vessel S1.

2. Tare weight of SS manufacturing vessel S2: Add dispensed quantity ofethanol absolute from total batch size in SS manufacturing vessel S2.

3. Where appropriate, add dispensed quantity of butylated hydroxyanisolein manufacturing vessel S2 step 2, stir well until clear solution isobtained.

4. Add dispensed quantity of amlodipine besylate in manufacturing vesselS2 step 3, stir well until hazy dispersion is obtained.

5. Add 2.0% of total batch size of glycerin in manufacturing vessel S2,stir well until clear solution is obtained.

6. Transfer the content of SS manufacturing vessel S2 of step 5, tovessel S1 of step 1. Stir well until clear homogeneous solution isobtained.

7. Add dispensed quantity of Lycasin 80/55 in manufacturing vessel S1step 6, stir well until clear solution is obtained.

8. Add dispensed quantity of frozen peppermint flavor in manufacturingvessel S1 step 7, stir well until clear solution is obtained.

9. Add remaining quantity of glycerin to make up the volume and stirredby overhead stirrer in SS manufacturing vessel S1.

10. Filter the solution using 40μ PP filter and filled in 150 mL Amberglass bottle with 28 mm CR cap.

Bottled formulations E-H were stored at 40±2° C. and 60%±5% RH for 3months and results for Impurity A are presented in Table 6.

TABLE 6 Stability Results of Formulations E-H Form. E Form. F Form GForm. H (no BHA) (0.1 mg/mL BHA) (0.2 mg/mL BHA) (0.4 mg/mL BHA)Parameters Initial 3M Initial 3M Initial 3M Initial 3M Impurity A ND0.55 ND 0.39 ND 0.37 0.22 0.26

As per the results presented in Table 6, the following observations werenoted:

-   (1) Impurity A increased to 0.55% after 3 months in Form. E (without    BHA).-   (2) Impurity A increased to 0.39% after 3 months in Form F (0.1    mg/mL BHA).-   (3) Impurity A increased to 0.37% after 3 months in Form G (0.2    mg/mL BHA).-   (4) Impurity-A increased to only 0.26% after 3 months from its    initial level of 0.22% in Form H (0.4 mg/mL BHA).    Effect of Co-Solvent Concentration on Liquid Solution of Amlodipine    with BHA as Antioxidant

Experiments were carried out to evaluate the effect of concentration ofco-solvent on the stability of the liquid solution of amlodipine. Threebatches were prepared with different concentration of ethanol (2%, 3%,and 4%) as summarized in Table 7.

TABLE 7 Compositional makeup of Formulations I-K. Formulation ID: Form.I Form. J Form. K Batch size: 2 L 2 L 2 L Quantity Quantity QuantityIngredients (mg)/mL (mg)/mL (mg)/mL Amlodipine Besylate† 2.77 mg 2.77 mg2.77 mg Liquid Maltitol 140.0 140.0 140.0 BHA 0.40 0.40 0.40 Ethanolabsolute 15.8 mg 23.7 mg 31.6 mg (0.02 mL/mL* (0.03 mL/mL* (0.04 mL/mL*or 2% v/v) or 3% v/v) or 4% v/v) Frozen peppermint 0.1 0.1 0.1 flavorGlycerin Qs to 1 mL Qs to 1 mL Qs to 1 mL †Equivalent to about 2 mg/mLamlodipine. *Based on ethanol density of 0.790 g/mL. Formulationdensity: 1.25 g/mL.

An exemplary process for preparing batches of Formulations I-Kcontaining the above-mentioned ingredients is as follows.

1. Tare weight of SS manufacturing vessel S1: Add 98% of total batchsize of glycerin in SS manufacturing vessel S1.

2. Tare weight of SS manufacturing vessel S2: Add specified quantity ofethanol absolute in SS manufacturing vessel S2.

3. Add dispensed quantity of butylated hydroxyanisole in manufacturingvessel S2 step 2, stir well until clear solution is obtained.

4. Add dispensed quantity of amlodipine besylate in manufacturing vesselS2 step 3, stir well until hazy dispersion is obtained.

5. Add 2% of total batch size of glycerin in manufacturing vessel S2,stir well until clear solution is obtained.

6. Transfer the content of SS manufacturing vessel S2 of step 5, tovessel S1 of step 1. Stir well until clear homogeneous solution isobtained.

7. Add dispensed quantity of Lycasin 80/55 in manufacturing vessel S1step 6, stir well until clear solution is obtained.

8. Add dispensed quantity of frozen peppermint flavor in manufacturingvessel S1 step 7, stir well until clear solution is obtained.

9. Add remaining quantity of glycerin to make up the volume 2 L (=2.5kg) and stirred by overhead stirrer in SS manufacturing vessel S1

10. Filter the solution using 40 μm PP filter and filled in 150 mL Amberglass bottle with 28 mm CR cap.

Observations with Respect to Formulations I-K

The batches prepared as per above composition were observed duringpreparation as well as after preparation.

As related to Formulation I, (2% v/v volume ethanol), amlodipine did notdissolve completely (more than 50%), and also at the end of batch morethan 20% amlodipine remain undissolved.

As related to Formulation J (3% v/v volume of ethanol), amlodipine didnot dissolve completely (more than 20-30%) and at the end of batch ittook very long time to get amlodipine dissolved.

As related to Formulation K (4% v/v volume of ethanol), amlodipinedissolved completely during process and remain dissolved afterpreparation and during observation for some time.

Preparation of Formulation L

TABLE 8 Compositional makeup of Formulation L Formulation ID:Formulation L Batch Size 5 L 6.25 kg Ingredients Quantity (mg/mL)Quantity (g/batch) Amlodipine besylate 1.385 6.925 Maltitol (Liquid)140.0 700.0 Butylhydroxyanisole 0.40 2.00 Ethanol, Absolute 31.6 mg 158(0.04 mL/mL*) Frozen Peppermint Flavor 0.1 0.5 Glycerin Qs to 1 mL Qs to5 L †Equivalent to about 1 mg/mL amlodipine. *Based on ethanol densityof 0.790 g/mL. Formulation density: 1.25 g/mL.

Batch Manufacturing Procedure for Formulation L.

1. Tare weight of SS manufacturing Vessel S1: Add 98% of total batchsize of glycerin SS manufacturing Vessel S1.

2. Tare weight of SS manufacturing Vessel S2: Add dispensed quantity ofethanol absolute from total batch size in SS manufacturing Vessel S2.

3. Add dispensed quantity of butylated hydroxyanisole in manufacturingVessel S2 step 2, stir well until clear solution is obtained.

4. Add dispensed quantity of amlodipine besylate in manufacturing VesselS2 step 3, stir well until hazy dispersion is obtained.

5. Add 2.0% of total batch size of glycerin in manufacturing Vessel S2,stir well until clear solution is obtained.

6. Transfer the content of SS manufacturing Vessel S2 of step 5, toVessel S1 of step 1. Stir well until clear homogeneous solution isobtained.

7. Add dispensed quantity of Lycasin 80/55 in manufacturing Vessel S1step 6, stir well until clear solution is obtained.

8. Add dispensed quantity of frozen peppermint flavor in manufacturingVessel S1 step 7, stir well until clear solution is obtained.

9. Add remaining quantity of glycerin to make up the volume and stirredby overhead stirrer in SS manufacturing Vessel S1.

10. Filter the solution using 40μ PP filter and filled in 150 mL amberglass bottle with 28 mm CR cap.

Bottled samples of Formulation L were stored at 40±2° C. and 75±5% RHand 25±2° C. and 60%±5% RH for 3 months and 6 months. Table 9 reportsobservations related to Description, AB Assay (by HPLC), BHA Assay (byHPLC), and Ethanol Assay (by GC) with respect to labeled content, aswell as the observed values for Impurity A, Single maximum unknownimpurity (“SMUI”), and Total Impurities (“Tot. Imps.”).

TABLE 9 Stability Results of Formulation L 40° C./ 25° C./ 40° C./ 25°C./ 75% RH 60% RH 75% RH 60% RH Parameters Specifications Initial 3M 3M6M 6M Description A clear pale Complies Complies Complies CompliesComplies straw colored, viscous liquid. AB Assay Between 90% 99.7% 98.2%100.6%  94.6% 98.0% and 110% of 1.358 mg/mL BHA Assay Between 70% 98.5%95.7% 99.3% 90.4% 93.3% and 110% of 0.40 mg/mL Ethanol Between 70% 91.1%92.6% 94.6% 94.0% 96.3% Assay and 110% of 31.6 mg/mL Organic impurities(By HPLC) Impurity A NMT 3.0% 0.22% 0.75% 0.26% 2.17% 0.63% SMUI NMT0.2% 0.04% 0.13% 0.04% 0.21% BQL Tot. Imps. NMT 3.5% 0.32% 1.09% 0.31%2.71% 0.63%

Amlodipine Oral Solution showed no significant change inphysico-chemical parameters during stability studies at 25±2° C./60±5%RH up to 6 months.

Preparation of Formulation M

TABLE 10 Compositional makeup of Formulation M Formulation ID: Form. MBatch size 180 L 180 L/225 kg Quantity Quantity per Ingredients (mg)/mLbatch Amlodipine Besylate† 1.385 mg 250.20 g Liquid Maltitol 140.0 25.20kg BHA 0.40 72.00 g Ethanol absolute 31.6* 5.69 kg Frozen peppermintflavor 0.10 18.00 g Glycerin ≈1076.5‡ 193.77 kg Qs to 1 mL †Equivalentto about 1 mg/mL amlodipine. *Based on ethanol density of 0.790 g/mL.‡Based on target density: 1.25 g/mL.

1. Tare weight of SS manufacturing vessel S1: Add about 91% of totalbatch size of glycerin in SS manufacturing vessel S1; mix liquid atabout 10 Hz under a vacuum of about 0.35 bar for about 10 minutes.

2. Tare weight of SS manufacturing vessel S2: Add specified quantity ofEthanol absolute in SS manufacturing vessel S2.

3. Add dispensed quantity of butylated hydroxyanisole in manufacturingvessel S2 step 2, stir for about 10 to about 15 min at about 30 Hz untilclear solution is obtained.

4. Add dispensed quantity of amlodipine besylate in manufacturing vesselS2 step 3, stir for about 10 to about 15 min at 30 Hz until hazydispersion is obtained.

5. Add about 2% of total batch size of glycerin in manufacturing vesselS2, stir for about 15 to about 25 min at 30 Hz.

6. If necessary, add a compensatory amount of ethanol to S2 whilestirring for about 1 to about 2 min at 30 Hz.

7. Transfer the content of SS manufacturing vessel S2 of step 5 (or step6), to vessel S1 of step 1. Stir well until clear homogeneous solutionis obtained.

8. Add about 2% of total batch size of glycerin in manufacturing vesselS2 (rinsing) while stirring at about 5 min to about 10 min at 40 Hz; andthen transfer contents of S2 to S1.

9. Add dispensed quantity of liquid maltitol (e.g., Lycasin 80/55) inmanufacturing vessel S1 step 8, stir for about 30 min to about 35 min at10 Hz.

10. Add dispensed quantity of frozen peppermint flavor in manufacturingvessel S1 step 9, stir at about 10 min to about 15 min at 15 Hz.

11. Add remaining quantity of glycerin to make up the volume 180 L=250kg and stirred by overhead stirrer from about 80 min to about 90 min at15 Hz.

10. Filter the solution using 40 μm PP filter and filled in 150 mL Amberglass bottle with 28 mm CRC/PP Cap, TE EPE lined.

Based on experience and literature support, amber-PET and amber-glassmaterial was selected for Amlodipine Oral Solution, which was readilyused in other approve marketed products and common for oral solutions.Comparative stability data at accelerated conditions of Amlodipine OralSolution stored in amber PET and amber glass bottle.

Based on data obtained during development, it was observed that aformulation described herein filled in Amber PET bottle with inductionseal (e.g., PP 28 child resistant closure with an IHS safe-guard 605liner-induction seal) showed a higher percent of Impurity A as comparedto product filled in amber glass bottle (see DMF No. 14003) with apharmaceutically acceptable closure (such as a 28 mm PolypropyleneTE-CRC cap with EPE liner, see DMF No. 18371). Impurity A in Amber PETbottle was found at a level of 1.05% when stored at 40° C./NMT 25% RHfor 3 months. Whereas, Impurity A in amber glass bottle was found to be0.58%, 40° C./75% RH after 3 months. Though both results meetspecifications, amber, glass bottles are selected as a viable commercialpackaging and will be used moving forward.

Bottled samples of three separate batches of Formulation M were storedat 40±2° C. and 75±5% RH for 6-months, 30±2° C./65±5% RH for 12-months,and 25±2° C. and 60%±5% RH for 18-months. Tables 11-13 reportobservations for a single batch (e.g., Formulation M, 180 L) related toAB Assay (by HPLC), BHA Assay (by HPLC), and Ethanol Assay (by GC) withrespect to labeled content, as well as the observed values for ImpurityA, Single maximum unknown impurity (“SMUI”), and Total Impurities (“Tot.Imps.”). In instances where the observed substance (or impurity) islower than the detection limit, reference is made to the acronym BLOQ

TABLE 11 Stability Results of Representative Batch of Formulation M at40 ± 2° C. and 75 ± 5% RH Test Specs. 1M (I) 2M (I) 3M (I) 3M (U) 6M (I)6M (U) AB Assay 100 ± 10% L.C. 100.0 99.3 99.1 99.4 98.6 98.7 BHA AssayNLT 70%; NMT 110% 99.2 98.6 97.0 98.6 96.5 98.5 EtOH Assay NLT 70%; NMT110% 101.2 101.8 96.9 96.9 98.2 97.7 Impurity A NMT 3% 0.23 0.38 0.520.28 0.75 0.35 SMUI NMT 0.2% 0.06 BLOQ 0.10 0.08 0.17 0.17 Tot. Imp. NMT3.5% 0.29 0.38 0.77 0.50 0.99 0.61

Tests (not shown) relate to density (specification of 1.23 to 1.28 g/mLwith an observed value of 1.255±0.002 g/mL) and description (a clearpale straw colored, viscous liquid (all time points comply). The batchcomplied with these additional tests when stored at 40±2° C. and 75±5%RH either upright or inverted.

TABLE 12 Stability Results of Representative Batch of Formulation M at30 ± 2° C./65 ± 5% RH The specifications are the same as thoseidentified in Table 11. Test 3M (I) 3M(U) 6M (I) 6M (U) 9M (I) 12M (I)12M (U) AB Assay 100.7 100.0 100.6 99.8 99.6 98.5 98.7 BHA Assay 99.399.4 98.3 98.4 98.4 95.8 96.3 EtOH Assay 97.9 96.8 98.1 96.8 101.9 99.698.5 Impurity A 0.20 0.19 0.37 0.29 0.55 0.81 0.60 SMUI 0.08 0.07 BLOQBLOQ 0.09 0.09 0.09 Tot. Imp. 0.34 0.26 0.37 0.29 0.85 0.90 0.70

Tests (not shown) relate to density (specification of 1.23 to 1.28 g/mLwith an observed value of 1.255±0.003 g/mL) and description (a clearpale straw colored, viscous liquid (all time points comply). The batchcomplied with these additional tests when stored at 30±2° C./65±5% RHeither upright or inverted.

TABLE 13 Stability Results of Representative Batch of Formulation M at25 ± 2° C. and 60% ± 5% RH The specifications are the same as thoseidentified in Table 11. 3M 3M 6M 6M 9M 12M 12M 18M 18M Test (I) (U) (I)(U) (I) (I) (U) (I) (U) AB Assay 100.4 100.6 99.4 99.5 100.0 100.0 99.699.2 99.4 BHA 99.6 100.0 99.0 98.7 99.8 97.6 97.5 96.6 97.4 Assay EtOH99.1 100.1 98.1 98.0 102.8 100.2 98.7 101.8 103.4 Assay Impurity 0.120.12 0.26 0.23 0.35 0.48 0.42 0.67 0.47 A SMUI 0.08 0.09 0.06 BLOQ 0.06BLOQ BLOQ BLOQ BLOQ Tot. Imp. 0.27 0.28 0.32 0.23 0.41 0.48 0.42 0.670.47

Tests (not shown) relate to density (specification of 1.23 to 1.28 g/mLwith an observed value of 1.254±0.002 g/mL) and description (a clearpale straw colored, viscous liquid (all time points comply). The batchcomplied with these additional tests when stored at 25±2° C. and 60%±5%RH either upright or inverted.

Bioequivalence Study

Pilot bioequivalence studies were performed comparing a formulation(viz., a representative batch of Formulation M, supra) with NORVASC®(amlodipine besylate) 10 mg tablets. A summary of the bioequivalencestudies are provided below.

Test Product: Amlodipine (1 mg/mL) Formulation

Listed Drug: NORVASC® (amlodipine besylate) 10 mg Tablets Pfizer Labs,Division of Pfizer Inc, NY, N.Y. 10017

Bioequivalence studies were undertaken in fasting adults (N=32).Pharmacokinetic parameters were derived individually for each analyzedsubject from the plasma concentration-time profiles of amlodipine.Actual time of blood sample collection was used for the estimation ofpharmacokinetic parameters. The mean pharmacokinetic parameters ofAmlodipine Oral Solution as the test product (T) and NORVASC® Tablets asthe reference product (R) have been summarized below in Table 14 andTable 15.

TABLE 14 Descriptive Statistics of Formulation Means for AmlodipineObtained by a Non-Compartmental Model (N = 32) Pharmacokinetic Mean ± SD(Un-transformed data) Parameters (Units) Test Product (T) ReferenceProduct (R) Cmax (ng/mL) 8.7619 ± 1.84919 8.3962 ± 1.79634 AUC0-72h(ng.hr/mL) 343.2637 ± 71.36683  325.6716 ± 62.47180  Kel (hr-1) 0.0141 ±0.00336 0.0144 ± 0.00316 t1/2 (hr) 52.3110 ± 14.64684 50.3930 ± 10.56366Tmax (hr) 6.469 ± 1.6798 6.172 ± 1.3947 Median Tmax (hr) 6.000 6.000

TABLE 15 Geometric Least Squares Means, Ratios and 90% ConfidenceIntervals for Pharmacokinetic Parameters (Cmax and AUC0-72h) ofAmlodipine (N = 33) (Including Outliers) Ln- transformed Geometric 90%Confidence Pharmacokinetic Least Squares Mean Interval Parameters TestReference T/R (Parametric) (Units) Product (T) Product (R) (%) LowerUpper Cmax (ng/mL)   8.5697   8.2147 104.32  99.20 109.71 AUC0-72h336.0381 319.9374 105.03 100.95 109.28 (ng.hr/mL)

The 90% confidence intervals of the differences of least squares meansfor the Ln-transformed pharmacokinetic parameters Cmax and AUC0-72 h ofamlodipine are within the bioequivalence acceptance limits of80.00-125.00%.

In view of the foregoing information, it is concluded that the testproduct (T), was found to be bioequivalent with reference product (R)NORVASC® (amlodipine) 10 mg Tablets of Pfizer Labs NY 10017 in healthy,adult, human subjects under fasting conditions.

A second study examined the food effect on the pharmacokineticparameters for the test product, Amlodipine Oral Solution. Subjects(N=31) were giving Amlodipine Oral Solution fasted and after a high-fat,high-calorie, non-vegetarian breakfast. Samples and statistical analysiswas handled in a similar fashion as the fasting study. A summary of theresults from the food effect study is listed in Table 16 and Table 17.

TABLE 16 Descriptive Statistics of Formulation Means for AmlodipineObtained by a Non-Compartmental Model (N = 31) Pharmacokinetic Mean ± SD(Un-transformed data) Parameters (Units) Test Product (Tfed) TestProduct (Tfast) Cmax (ng/mL) 8.5176 ± 1.58377 8.7179 ± 1.39330 AUC0-72h(ng.hr/mL) 348.9069 ± 63.16044  345.1714 ± 63.17824  Tmax (hr) 6.550 ±2.1351 7.290 ± 2.1709 Median Tmax (hr) 6.000 7.500

TABLE 17 Geometric Least Squares Means, Ratios and 90% ConfidenceIntervals for Pharmacokinetic Parameters (Cmax and AUC0-72h) ofAmlodipine (N = 31) (Including Outliers) Ln- transformed 90% GeometricLeast Squares Mean Confidence Test Test Tfed/ Interval PharmacokineticProduct Product Tfast (Parametric) Parameters (Units) (Tfed) (Tfast) (%)Lower Upper Cmax (ng/mL)   8.3748   8.6192  97.16 93.13 101.38 AUC0-72h(ng.hr/mL) 343.2017 339.7738 101.01 97.02 105.16

The 90% confidence intervals of the differences of least squares meansfor the Ln-transformed pharmacokinetic parameters Cmax and AUC0-72 h ofamlodipine are within the acceptance limits of 80.00-125.00%.

In view of the foregoing information, it is concluded that there is nofood effect observed for the test (T) product (Dose: 10 mL equivalent tothe dose of 10 mg of amlodipine) in healthy, adult, human subjects underfed versus fasting conditions. These clinical results are consistentwith the dissolution results of amlodipine in FaSSIF and FeSSIFdissolution media (not shown).

Additional Formulations

Formulations without added ethanol were evaluated for furtherconsideration. Table 18 summarizes the compositional makeup of threeformulations without ethanol (Formulations N-P).

TABLE 18 Compositional makeup of Formulations N-P Formulation ID: Form.N Form. O Form. P Amount Amount Amount Ingredients (g) % w/w (g) % w/w(g) % w/w Amlodipine Besylate 0.277 0.136 0.277 0.112 0.277 0.127MagnaSweet — — — — 0.400 0.183 Liquid Maltitol — — 28 11.360 — — BHA0.080 0.039 0.080 0.032 0.080 0.037 Propylene Glycol 14.3 7.004 28.611.604 28.6 13.067 Mixed Berry Flavor 0.020 0.010 0.020 0.008 0.0200.009 Glycerin 189.5 92.812 189.5 76.883 189.5 86.578 Δ Assay (%) 8.08.7 11.3 Tot. Imps. (%) 2.1 2.7 2.8

A preliminary (i.e., non-validated) study was performed by storingsamples of Formulations N-P for 6-weeks at 60° C. and by evaluating thesamples for amlodipine besylate assay and total impurities.

The results of the study showed that amlodipine besylate assay after6-weeks (“A Assay”) was reduced by only about 8% for Formulation N,while amlodipine besylate assay was reduced by about 11.3% forFormulation P.

The results of the study also showed that the amount of total impurities(“Tot. Imps.”) increased by about 2.1% for Formulation N, while totalimpurities increased by about 2.8% for Formulation P.

The results observed for Formulation N (with no added water) showed thatan amlodipine besylate formulation substantially free of water (viz.,having a water content of about 0.01% w/w or lower) showed improvedstability compared to other formulations (e.g., Formulation P)containing water.

One will appreciate the Arrhenius kinetic model states that generallyfor every 10° C. change in temperature, then the degradation ratechanges by a factor of two. That said, and working under the assumptionthat amlodipine degradation follows an Arrhenius kinetic model, it isestimated that Formulation N has shelf-life of at least about 17 months,while Formulation 0 has a shelf-life of at least about 20-months whensamples are stored at 25±2° C. and 60%±5% RH. Additional data maysupport a specification of 100±10% labeled claim stability for at least24-months when bottled samples are stored at 25±2° C. and 60%±5% RH.

Practical Utility

The formulations disclosed herein show practical utility with respect tolong-term stability and content uniformity.

The liquid formulations disclosed herein exhibit improved propertiescompared to the commercially marketed KATERZIA® suspension productbecause there is no need to refrigerate to maintain a suitableshelf-life of up to 24-months. Additionally, there would be no concernwith respect to content uniformity for the liquid formulations disclosedherein compared to the KATERZIA® suspension product.

The formulations disclosed herein are superior to the Mandalformulations, which included added water of about 11% w/w, and showedreduced amlodipine stability.

The liquid pharmaceutical formulation substantially free of water(and/or ethanol), comprising: (i) 100±10% labeled content when storedfor about 24-months at 25±2° C. and 60±5% relative humidity; (ii)100±10% labeled content when stored for about 18-months at 25±2° C. and60±5% relative humidity; (iii) 100±10% labeled content when stored forabout 12-months at 25±2° C. and 60±5% relative humidity; (iv) 100±5%labeled content when stored for about 24-months at 25±2° C. and 60±5%relative humidity; (v) 100±5% labeled content when stored for about18-months at 25±2° C. and 60±5% relative humidity; (vi) 100±5% labeledcontent when stored for about 12-months at 25±2° C. and 60±5% relativehumidity; (vi) 100±5% labeled content when stored for about 12-months at30±2° C. and 65±5% relative humidity; and/or (vii) 100±5% labeledcontent when stored for about 6-months at 40±2° C. and 75±5% relativehumidity. These findings are particularly surprising considering thatNoburu plainly states that amlodipine besylate is incompatible withglycerin.

Based on a review of the exemplified embodiments disclosed herein, onemay appreciate that a formulation disclosed herein does not contain asurfactant. Thus, contemplated herein is a liquid pharmaceuticalformulation substantially free of water (and/or ethanol), that containsno surfactant.

One may appreciate that the expression “comprising” may be replaced withthe expression “consisting of” to reflect a formulation disclosedherein.

Cited Information

Berge et al., Pharmaceutical Salts, J. Pharm. Science (1977) 66(1): 1-19(“Berge”).

Handbook of Pharmaceutical Excipients, Sixth Edition (2009), Rowe et al.Eds. (“Handbook”).

JP 2009-256216 A, Liquid amlodipine besylate formulation for internaladministration stable in solution state, to Noboru et al. of TowaYakuhin KK (“Noburu”).

KATERZIA® (amlodipine) oral suspension, for oral use, prescribinginformation as of Jul. 8, 2019 (“KATERZIA® Label”).

Murakami et al., Application of liquid chromatography-two-dimensionalnuclear magnetic resonance spectroscopy using pre-concentration columntrapping and liquid chromatography—mass spectrometry for theidentification of degradation products in stressed commercial amlodipinemaleate tablets, J. Chromatog. A (2008) 1181 (1-2): 67-76 (“Murakami”).

Nahata et al., Stability of Amlodipine Besylate in Two Liquid DosageForms, J. Am. Pharm. Assoc. (1999) 39: 375-377 (“Nahata”).

NORVASC® (amlodipine besylate) tablets for oral administrationprescribing information, as of Oct. 30, 2017 (“NORVASC® Label”).

Ragno et al., Photodegradation monitoring of amlodipine by derivativespectrophotometry, J. Pharm. Biomed. Anal. (2002) 27(1): 19-24(“Ragno”).

Rapolu et al., Isolation and characterization of a novel aciddegradation impurity of Amlodipine Besylate using Q-TOF, NMR, IR andsingle crystal X-ray, J. Pharm. Biomed. Anal. (2014) 99: 59-66(“Rapolu”).

Stopher et al., The Metabolism and Pharmacokinetics of Amlodipine inHumans and Animals, J. Cardiovasc Pharmacol. (1988) 12 (Suppl. 7):S55-S59 (“Stopher”).

UK Patent Application GB 2 166 637 A, Drink Concentrate, to LeslieWilliam David of Powell & Scholefield Limited (“Dodd”).

U.S. Pat. No. 4,879,303, Pharmaceutically Acceptable Salts, to Davisonet al. of Pfizer (“Davison”).

U.S. Pat. No. 7,108,885, Liquid Maltitol Composition, Process for itsManufacture and its Uses, to Michel Serpelloni of Roquette Freres(“Serpelloni”).

U.S. Pat. No. 10,695,329, Amlodipine Formulations, to Brauer et al. ofSilvergate Pharmaceuticals, Inc. (“Brauer”).

U.S. Patent Application Publication No. 2011/0294860 A1, Aqueous OralPreparation of Stable Amlodipine, to Tatsumi et al. of MedRx Co. Ltd.(“Tatsumi”).

U.S. Patent Application Publication No. 2018/0303811 A1, Oral Solutionof Dihydropyridine Derivatives, Mandal et al., of FTF Pharma PrivateLimited (“Mandal”).

Alternative embodiments, examples, and modifications which would stillbe encompassed by the disclosure may be made by those skilled in theart, particularly in light of the foregoing teachings. Further, itshould be understood that the terminology used to describe thedisclosure is intended to be in the nature of words of descriptionrather than of limitation.

As stated above, this application claims priority to U.S. ProvisionalPatent Application No. 63/144,021, filed on Feb. 1, 2021, the entiresubject matter of which is incorporated by reference.

The references and documents described herein are incorporated byreference in their entirety to the extent necessary. If there is adifference in meaning between the incorporated terms and the termsdisclosed herein, the meaning of the terms disclosed herein willcontrol.

Those skilled in the art will also appreciate that various adaptationsand modifications of the preferred and alternative embodiments describedabove can be configured without departing from the scope and spirit ofthe disclosure. Therefore, it is to be understood that, within the scopeof the appended claims, the disclosure may be practiced other than asspecifically described herein.

The invention claimed is:
 1. A liquid pharmaceutical formulation,comprising: about 0.10% w/w to about 0.12% w/w of amlodipine besylate,at least one pharmaceutically acceptable excipient, and a vehiclecomprising about 80% w/w to about 96% w/w glycerin; wherein the liquidpharmaceutical formulation has a water content of less than or equal toabout 5% w/w.
 2. The formulation of claim 1, wherein the at least onepharmaceutically acceptable excipient comprises about 4% w/w to about 7%w/w of a sweetening agent; about 0.01% w/w to about 0.05% w/w of anantioxidant; optionally about 0.006% w/w to about 0.010% w/w of aflavoring agent; optionally about 2% w/w to about 4% w/w ethanol.
 3. Theformulation of claim 1, wherein the at least one pharmaceuticallyacceptable excipient comprises about 4% w/w to about 7% w/w of asweetening agent; about 0.03% w/w to about 0.04% w/w of an antioxidant;optionally about 0.006% w/w to about 0.010% w/w of a flavoring agent;optionally about 2% w/w to about 4% w/w ethanol.
 4. The formulation ofclaim 1 comprising about 0.11% w/w of amlodipine besylate; wherein theat least one pharmaceutically acceptable excipient comprises about 4%w/w to about 7% w/w of a sweetening agent; about 0.01% w/w to about0.05% w/w of an antioxidant; optionally about 0.006% w/w to about 0.010%w/w of a flavoring agent; optionally about 2% w/w to about 4% w/wethanol.
 5. The formulation of claim 1 comprising about 0.11% w/w ofamlodipine besylate; wherein the at least one pharmaceuticallyacceptable excipient comprises about 4% w/w to about 7% w/w of asweetening agent comprising maltitol; about 0.01% w/w to about 0.05% w/wof an antioxidant comprising butylated hydroxyanisole; optionally about0.006% w/w to about 0.010% w/w of a flavoring agent; optionally about 2%w/w to about 4% w/w ethanol.
 6. The formulation of claim 1 comprisingabout 0.11% w/w of amlodipine besylate; wherein the at least onepharmaceutically acceptable excipient comprises about 5% w/w to about 7%w/w of a sweetening agent comprising maltitol; about 0.03% w/w of anantioxidant comprising butylated hydroxyanisole; optionally about 0.008%w/w to about 0.010% w/w of a flavoring agent; optionally about 2% w/w toabout 4% w/w ethanol.
 7. The formulation of claim 1 comprising about0.11% w/w of amlodipine besylate; wherein the at least onepharmaceutically acceptable excipient comprises about 5% w/w to about 7%w/w of a sweetening agent comprising maltitol; about 0.03% w/w of anantioxidant comprising butylated hydroxyanisole; optionally about 0.008%w/w to about 0.010% w/w of a flavoring agent; about 2.5% w/w ethanol;and wherein the vehicle comprises about 80% w/w to about 92% w/wglycerin.
 8. The formulation of claim 1 comprising about 0.11% w/w ofamlodipine besylate; wherein the at least one pharmaceuticallyacceptable excipient comprises about 6% w/w of a sweetening agentcomprising maltitol; about 0.03% w/w of an antioxidant comprisingbutylated hydroxyanisole; about 0.008% w/w to about 0.010% w/w of aflavoring agent; about 2.5% w/w ethanol; and wherein the vehiclecomprises about 80% w/w to about 92% w/w glycerin.
 9. The formulation ofclaim 1 comprising about 0.11% w/w of amlodipine besylate; wherein theat least one pharmaceutically acceptable excipient comprises about 11%w/w of a liquid maltitol syrup comprising maltitol; about 0.03% w/w ofan antioxidant comprising butylated hydroxyanisole; about 0.008% w/w toabout 0.010% w/w of a flavoring agent; about 2.5% w/w ethanol; andwherein the vehicle comprises about 80% w/w to about 92% w/w glycerin.10. A container comprising written material and a bottle comprising theformulation of claim
 1. 11. A method for the treatment of a condition,which comprises administering to a patient in need thereof atherapeutically effective amount of the formulation of claim 1; whereinthe condition is treatment of hypertension, the symptomatic treatment ofchronic stable angina, the treatment of vasospastic angina, or thetreatment of a coronary artery disease; and wherein the patient is anadult patient or a pediatric patient.
 12. A method for the treatment ofa condition, which comprises administering to a patient in need thereofa therapeutically effective amount of the formulation of claim 1,wherein the condition is treatment of hypertension; and wherein thepatient is an adult patient or a pediatric patient.
 13. A method for thetreatment of a condition, which comprises administering to a patient inneed thereof a therapeutically effective amount of the formulation ofclaim 1; wherein the condition is the symptomatic treatment of chronicstable angina; and wherein the patient is an adult patient or apediatric patient.
 14. A method for the treatment of a condition, whichcomprises administering to a patient in need thereof a therapeuticallyeffective amount of the formulation of claim 1; wherein the condition isthe treatment of vasospastic angina; and wherein the patient is an adultpatient or a pediatric patient.
 15. A method for the treatment of acondition, which comprises administering to a patient in need thereof atherapeutically effective amount of the formulation of claim 1; whereinthe condition is treatment of a coronary artery disease; and wherein thepatient is an adult patient or a pediatric patient.
 16. The formulationof claim 1, wherein the liquid pharmaceutical formulation has a watercontent of less than or equal to about 4% w/w.
 17. The formulation ofclaim 1, wherein the liquid pharmaceutical formulation has a watercontent of less than or equal to about 3% w/w.
 18. The formulation ofclaim 9, wherein the liquid pharmaceutical formulation has a watercontent of less than or equal to about 4% w/w.
 19. The formulation ofclaim 9, wherein the liquid pharmaceutical formulation has a watercontent of less than or equal to about 3% w/w.